Method of treating conditions of teeth and their supporting tissue with sucralfate

ABSTRACT

The use of a sulphated saccharide or a salt or a complex thereof as an ingredient in a topical preparation for the prophylaxis or treatment of diseases or conditions of the tooth or tooth-supporting tissue, in particular for the prophylaxis or treatment of inflammatory and plaque-related conditions, a method of preventing or treating such diseases or conditions by topically applying the sulphated saccharide or salt or complex thereof, and a topical preparation containing the sulphated saccharide or salt or complex thereof for the prophylaxis or treatment of such diseases or conditions. The sulphated saccharide is especially a polysulphated or persulphated saccharide. e.g. sucralfate (sucrose octakis(hydrogen sulphate) aluminum complex) or a sodium and/or potassium salt of sucrose octakis(hydrogen sulphate). The preparation may be in the form of a solution, suspension, salve, paste, powder, gel, cream, dental fixative, periodontal implant, chewing gum, chewable tablet, effervescent tablet or lozenge.

This application is a continuation, of application Ser. No. 07/375,006,filed Aug. 4, 1989 now abandoned.

FIELD OF INVENTION

The present invention relates to the use of sulphated saccharides forthe treatment of conditions of teeth and tooth-supporting tissue.

TECHNICAL BACKGROUND

Both gingivitis and periodontitis are inflammatory diseases caused byplaque formation on the teeth. Chronic periodontitis often leads todestruction of the tissues supporting the teeth. Plaque can be definedas a soft bacteria-containing coating on the surface of a tooth. When atooth is not clean, plaque formation will commence and this will lead togingivitis in the gingival area.

The inflammation of the gingiva leads to the formation of the gingivalsulcus, and a gingival pocket is formed. Clear evidence that plaque isresponsible for gingivitis was derived from the induction ofexperimental gingivitis (H. Loe et al., J. Periodontology 36: 177-187,1965). Starting from a state of clinical gingival health, allparticipants developed gingivitis within 10 to 21 days after eliminationof oral hygiene procedures. After reinstating plaque control, thegingiva returned to a normal condition within seven days.

Gingivitis is characterized by swelling and redness of the free gingivalmargin. Bleeding is caused by, for example, toothbrushing and gentleprobing by a dentist. There is a loss in the connective tissue tone,which tends to open the gingival sulcus. The disease process may becombatted by either eliminating the plaque or by altering theenvironment by changing the composition of the plaque.

In order to colonize a surface, bacteria must be able to adhere to thesurface in question. The mucous epithelium of the oral cavity isconstantly renewed, so that bacteria adhering to the mucosal surfacewill tend to be sloughed off together with the outer layer of dead cellsof the epithelium, thus preventing bacterial invasion of the livingtissue underneath the dead epithelial cells. On the other hand, thedental surface constitutes a firm non-living base to which bacteriaeffectively adhere. The bacterial colonies on the dental surface(plaque), especially at the gingival margin and in the subgingivalregion, are not removed by any similar process, resulting in anantibacterial immune reaction from the surrounding tissue evident as achronic inflammation of the gingival tissue. Under normal and healthyconditions this inflammatory reaction is mild, with a delicate balancebeing struck between colonizing bacteria and antibacterial effect.

Inflammation of the gingiva due to bacterial colonization of the dentalsurfaces is therefore an important initial stage of periodontitis. Ifthe bacterial colonies (plaque) are not removed, accumulation ofbacteria along the gingival margin or in the dento-gingival region willlead to increased gingival inflammation and destruction of theperiodontal membrane possibly followed by bone resorption. Eventually aperiodontal pocket develops in which more bacteria accumulate, resultingin increased inflammation and infection proper of the tissue so as tolead to a more pronounced degradation of the tooth-supporting tissue.

Wherever there is a plaque coated surface, calcium ions can take part inchemical reactions, giving rise to formation of calculus. Calculus canbe found on the tooth surface as supra-gingival or subgingival deposits.These deposits must be removed in order to maintain normal gingivalconditions.

A characteristic of periodontal infection is that once bacteria/plaquehave established themselves (i.e. infected) firmly in a periodontalpocket, the natural humoral defense mechanisms are not capable ofdealing with the infection, and the plaque may turn into hard deposits,i.e. calculus.

Apart from the general inflammation caused by the presence ofbacteria/plaque, the release of hydrolytic enzymes like hyaluronidase,desoxyribonuclease, collagenase and protease probably contributes to thedestruction of dental tissue.

The severity of tissue damage probably depends on the antigen/antibodyreaction of the organism as well as the degree of retention ofinflammatory products in the periodontal pockets. Accumulation ofmediators of local inflammation accelerates the process. In most casesthe process is slow, with immunoinfiltration of the gingival tissue andformation of granulation tissue which contains inflammatory cells.Occasionally, this slow progression is superseded by acute exacerbationswith accumulation of inflammatory cells and release of lysosomalenzymes. Such exacerbations are probably due to changes in the bacterialflora.

Juvenile periodontitis differs from the above marginal periodontitisonly by an early onset, and by often involving certain groups of teethand being accompanied by a much lesser degree of plaque formation. Itbegins in late childhood, resulting in a pronounced loss of the teeth'ssupporting tissue, and it too is an infectious disease on a par withother periodontal diseases.

Current periodontal therapy is directed towards the removal of bacterialplaque and calculus deposits--subgingival and supragingival plaque.These goals are usually achieved by means of scaling and polishing,instruction in oral hygiene procedures, periodontal surgery whereindicated and periodic maintenance.

Another option for treatment which remains to be fully evaluated is thepossibility of disrupting the subgingival microflora in such a way thatsupragingival plaque control becomes less important. One potentialapproach to such a treatment is intensive intermittent disruption usinglocal or systemic antimicrobial agents, examples of which aremetronidazole, tetracycline and erythromycin. Such agents may also beused for irrigation of the periodontal pockets. The potential effect isbased on the concept that alteration of the subgingival microflora atappropriate intervals may be sufficient to prevent the development of anecosystem suitable to the reestablishment of pathogens in adequatelevels for disease initiation. Another approach is bacterialsubstitution, replacing potential pathogens with bacteria which occupythe same ecological niche but have a reduced pathogenic potential.

Still another approach is the use of chemical agents which will alterplaque and subgingival microflora sufficiently to prevent gingivitis orthe development of gingivitis into periodontitis.

A vast number of chemical agents have been evaluated as potentialantiplaque/antigingivitis agents. The first generation agents areantibacterial agents with limited effectiveness. These agents areeffective as antibacterials in vitro, but are either not retainedintra-orally or they are rapidly released. Therefore, they inhibit thebacteria for a short period of time, after which time bacteria growth isresumed. Their clinical effect is limited unless the agents are usedfrequently, i.e. four to six times a day. This group includes topicalantibiotics, oxygenating compounds, quaternary ammonium compounds,phenolic compounds, and sanguinarine. The second generation agents areeffective not only in vitro but also in vivo, due to their retention andrelease kinetics. At present, chlorhexidine and chlorhexidine analoguesare the primary second generation compounds, and stannous fluoride mayalso qualify as belonging to this group.

Penicillin, tetracycline, erythromycin, polymyxin B, kanamycin,metronidazole and spiromycin have been used for anti-plaque treatment.However, the potential for the development of bacterial resistance andhypersensitivity reactions should limit the use of antibiotics forplaque control purposes. In general, antibiotics may hold great promisefor specific bacterial diseases in the oral cavity, but they appear tobe inappropriate for the routine control of supragingival plaque andassociated diseases.

Quaternary ammonium compounds are cationic surface agents which arecapable of reducing surface tension, absorbing to negatively chargedsurfaces and disrupting membranes. Plaque reducing effects have beenreported with benzethonium chloride and cetylpyridinium chloride at 0.1%when used four times daily. Side effects with quaternary ammoniumcompounds have included both ulcerations and discomfort.

Phenolic compounds have a long history of use in the oral cavity aseither a mouthwash or as throat lozenges. A commercial preparation(Listerine®) of thymol, eucalyptol, methyl salicylate, benzoic acid andboric acid has shown a certain plaque reducing effect as compared to aplacebo. It is not clear whether the degree of plaque inhibition due tothis agent is of long-term value in the prevention of parodontitis.

Sanguinarine, a benzophenanthradine alkaloid, has recently been reportedto be potentially useful as a plaque control agent. Preliminary studiesindicate that sanguinarine is capable of providing some reduction andprevention of plaque and gingivitis.

Chlorhexidine gluconate in 0.1-0.2% solutions and 1% gels have beenshown to exert an effective plaque inhibiting and anti-gingivitiseffect, when used short-term. A few long-term studies with chlorhexidinegluconate have also shown promising effects against plaque formation.The oral use of chlorhexidine has been associated with staining of theteeth and tongue and a bitter taste, and longer use often gives rise toalterations of the mucosa. Owing to the cationic nature of the compound,it is difficult to mask the taste by addition of flavoring agentswithout affecting the biological activity. Other agents such asalexidine and octenidine are structurally similar to chlorhexidine, andappear have a comparable effect.

In summary, treatment of gingivitis and periodontitis has mainly beenprophylactic, emphasizing the importance of removing calculus and dentalplaque and generally improving oral hygiene by mechanical means such astoothbrushing using fluoride-containing toothpastes etc., and usingdental floss, toothpicks and the like. When necessary, surgical methodshave been used in order to reduce the depth of the periodontal pockets.Systemic or topical antibacterial treatment with tetracycline or thelike has also been shown to have some effect, especially during acuteinfectious episodes, and finally, irrigating or rinsing the mouth withantiseptics such as chlorohexidine has been shown to exert a certain, iflimited, effect, especially on gingivitis and plaque formation. However,none of these treatments are entirely satisfactory as they eitherrequire a high degree of patient compliance and/or do not possess a highdegree of efficiency.

SUMMARY OF THE INVENTION

It has surprisingly been found that sulphated saccharides, in particularsucralfate, exert a highly beneficial effect on a variety of dentalconditions and diseases when applied topically on teeth or gingiva.

Accordingly, in one aspect, the present invention relates to the use ofa sulphated saccharide or a salt or a complex thereof as an ingredientin a topical preparation for the prophylaxis or treatment of diseases orconditions of the tooth or tooth-supporting tissue. In the following,such diseases or conditions are occasionally referred to as dentaldiseases or conditions.

In contradistinction to the known means of treating or preventing dentalconditions, excellent results have been obtained according to thepresent invention, by using a sulphated saccharide such as sucralfate,in connection with diseases such as gingivitis, periodontitis,alveolitis, and infections such as oral candida.

Sucralfate has previously been indicated for the treatment of gastricand duodenal ulcers (cf. U.S. Pat. No. 3,432,489; EP 161816; EP 192640)and for the treatment of emesis and diarrhoea in dogs and cats (cf. EP133880). In radiolabelled form, sucralfate has also been used as adiagnostic agent for the imaging of gastrointestinal mucosa since, asmentioned above, the substance binds selectively to ulcerated areas inthe stomach and upper small intestine (cf. EP 107209).

The American Journal of Gastroenterology, 80(3), 1985, pp. 206-209;"Sucralfate: Nonulcer Uses" suggests the use of sucralfate for a varietyof applications apart from the treatment of gastric and duodenal ulcer,including the treatment of chemotherapy induced stomatitis 6 gsucralfate/15 ml glycerol), post-sclerotic ulcer, reflux oesophagitisand bile reflux oesophagitis as well as for counteracting theulcerogenic effects of aspirin. Also, Ferraro and Mattern, Drug Intell.Clin. Pharm. 18, 1984, p. 153, report the use of a sucralfate suspensionfor treating chemotherapy-induced mouth ulcers (stomatitis), utilizingthe ability of sucralfate to adhere to ulcers (vide above). However, theis no indication that sucralfate may be used for other purposes thantreating mucosal ulcers. Similarly, EP 136 100 suggests the possible useof a sucralfate suspension for treating ulcers in the mouth but does notindicate any non-ulcer use of the substance.

EP 230 023 describes pharmaceutical compositions comprising sulphatedoligosaccharides for wound healing. This disclosure indicates the use ofthese substances for the enhancement of healing of wounds in collagencontaining tissues, including skin and bone. It refers in particular toskin ulcers characterized by breaches or ruptures of the skin barrier.It is stated in the disclosure that polysulphated saccharides arebelieved to be involved in the stimulation of migration of repair cells,such as fibroblasts, into the wound site, resulting inneovascularization. It is further stated that sucralfate gives rise toinflammatory reactions, and that wound healing with neovascularizationand fibroblast (rather than macrophage) migration was not observed withsucralfate. It is also stated that a low level of 0.1 to 1 mg/ml of thepolysulphated saccharide is preferred in order to avoid local haemorrageor inflammation at the wound side. In contradiction to this, excellentanti-inflammatory effects have been obtained according to the presentinvention by using sucralfate topically on the gingiva. The disclosurealso mentions that polysulphated saccharides may be used to promote bonehealing, and that because of this healing effect they are believed to besuitable for use in or as prosthesic devices, for treatment ofperiodontal disease and in artificial skin. Periodontal disease in thiscontext would seem to be speculatively listed because of the claimedbone healing effect.

Thus, the above references do not indicate that sucralfate or otherpolysulphated saccharides exert anti-inflammatory effects, antiplaqueeffects, or that they stabilize or strengthen cell surfaces andintercellular matrices, including the epithelial and mucosal surfaces.On the contrary, the above mentioned EP 230 023 states that sucralfateactually contributes to inflammation. In view of the results hithertoobtained, which show binding of sucralfate to wounded mucosal surfaces,it is considered surprising that sucralfate, and probably the entiregroup of polysulphated saccharides, may be used for indications notinvolving wounded or ulcerated oral mucosa, but rather inflammatorydiseases such as gingivitis and periodontitis, and for preventing plaqueand calculus formation in the gingival pocket.

It has been observed that one sulphated saccharide, sucralfate, whenused internally in the treatment of gastric ulcers, binds preferentiallyto the surface of the ulcer. It is currently believed that this is aproperty which is common to sulphated saccharides and that it is theresult of an ability of sulphated saccharides to bind to proteoglycansand hyaluronic acid, which are the components of the surface of manycells and protect or stabilize them so that the cell surface remainsintact. In other cases, e.g. in connective tissue, including gingiva,hyaluronic acid and proteoglycans form a protective matrix in whichcells are embedded. Furthermore, it is known that certain sulphatedsaccharides, e.g. heparan sulphate, dextran sulphate and xylosesulphate, are hyaluronidase inhibitors. Hyaluronidases are enzymes whichcatalytically cleave the glycosidic bonds of hyaluronic acid. Thedecomposition of hyaluronic acid by hyaluronidases therefore leads toexposure of the cells to damage from various agents such as pathogensand inflammatory substances. It has been demonstrated (P. M. Bartold andR. C. Page, J. Oral Path. 15, 1986, pp. 367-374; K. S. Last et al.,Archs Oral Biol. 30 (3), 1985, pp. 275-281) that the presence ofdegradation products of hyaluronic acid in cervicular fluid present inthe periodontal pockets are correlated with clinical signs ofperiodontitis. Thus, it is assumed that by inhibiting hyaluronidase,sulphated saccharides promote the regeneration of tissue by promotingthe regeneration of the layer of matrix containing hyaluronic acid andproteoglycans. Sulphated saccharides such as sucralfate may also modifyor inhibit inflammatory reactions and/or stimulate tissue regenerativeprocesses by other not yet fully understood mechanisms.

The non-aluminium complexed form of sucralfate is a salt of sucroseoctakis(hydrogen sulphate), which is a very strongly negatively chargedentity. It is contemplated that the effects of sucralfate and othersulphated saccharides can in part be ascribed to these strongelectrostatic forces. They may be important in preventing pellicleformation on tooth surfaces, and they may also play an important role inthe modification and protection of the cell surface. It is believed thata normal or healthy cell surface has a strong electro-negative charge,which is disturbed when the cell surface is impaired. Sucroseoctakis(hydrogen sulphate) salts and other sulphated saccharide moietiesmay act as electronegative charges which can reestablish the negativesurface charge of the "wounded cell area", and thereby exert a cellprotecting, wound healing and anti-inflammatory effect.

Vitamin C and sucralfate would seem to be related in several aspects.Chemically, they are both structurally related to glucose and otherhexoses. At the tissue level, both compounds are associated with thesynthesis of intercellular substances, including collagen, and it isknown that vitamin C stimulates the synthesis of sulphatedproteoglycans. Depletion of vitamin C leads to scurvy, which ischaracterized by, among other things, impaired wound healing andgingivitis. In clinical studies it has been possible to demonstrate aclose relationship between gingivitis and vitamin C intake. Sucralfatehas been demonstrated to enhance wound healing and to improve gingivitiswhen applied topically. Recently, vitamin C has also been associatedwith immunoenhancing, anti-inflammatory and anti-allergic effects. Theanti-inflammatory effect of vitamin C is, among other things, a resultof inhibition of myeloperoxidase and aryl sulphatase activity, andpossibly also the elimination of free radicals. It is contemplated thatsucralfate may possess the same properties as vitamin C with respect toantioxidant effect and inhibition of myeloperoxidase and other enzymeswhich play a role in inflammatory processes.

Sucralfate has been shown to have a plaque reducing and modifying effectwhen used topically in the oral cavity. The mechanisms involved information of plaque are still little understood. The adhesiveinteraction involved in plaque formation appears to be very complex, asmay be deduced a prior from the wide variations in the chemicalcomposition of the acquired pellicle and interbacterial matrix. Theconstituents of saliva, such as high molecular glycoproteins, may playan important role in the removal of bacteria from the mouth byinhibiting bacterial attachment to oral surfaces. These findings (Embery& Sdhogg, Proc. of a workshop on saliva-dental plaque and enamel surfaceinteractions, Strasbourg, Ed. R. M. Frank & S. A. Leach, pp. 185-194,October 1981) suggest that saliva, by mimicing the bacterial bindingsites on teeth and the epithelial cell surfaces, may competitivelyinhibit bacterial attachment. It is contemplated that sucralfate, via amodulating/stimulating effect on glucosaminoglycanes and hyaluronic acideither directly or via inhibition/stimulation of various enzymes,enhances the ability of salivary components to mask bacterial bindingsites and to induce bacterial aggregation, thereby diminishing orpreventing plaque formation, in the gingival sulcus/pocket. Lectin-likeinteractions also appear of importance in the aggregation and attachmentof oral bacteria. It has furthermore been observed that there is asimilarity between the GAG (glycosaminoglycans) in mixed dental plaqueand calculus and gingival tissues, suggesting that periodontal breakdownmay be a factor in the accumulation of GAG in subgingival calculus.Inhibition of GAG breakdown by sucralfate will thus prevent theformation of plaque and calculus. Furthermore, the group of compoundsbelonging to the glycosaminoglycanes has proved to be a useful modelseries with which to study the binding properties of hydroxyapatite. Thebinding of hydroxyapatite is enhanced by calcium ions and inhibited byfluoride, and it is electrostatic in nature. It is therefore notunlikely that modifications of GAG's by sucralfate and otherpolysulphated saccharides can interfere with initial pellicle formationand the binding of bacteria to the surface of the teeth.

In a further aspect, the present invention relates to a method ofpreventing or treating dental diseases or conditions, the methodcomprising topically applying on teeth or tooth-supporting tissue, aprophylactically or therapeutically effective amount of a sulphatedsaccharide or a salt or a complex thereof.

DETAILED DISCLOSURE OF THE INVENTION

The sulphated saccharide used in accordance with the invention may be amonosaccharide, for instance xylose, fructose or glucose, anoligosaccharide, in particular a disaccharide such as sucrose, lactose,maltose or cellobiose, or a polysaccharide such as dextran, heparan,dermatan, proteodermatan, hyaluronic acid, heparin, chondroitin,amylose, glucosamine, glucosaminoglycan and a mucopolysaccharide or asubunit thereof.

In certain cases, it may be an advantage to use the sulphated saccharidein combination with another wound-healing substance such as anon-sulphated polysaccharide, for instance hyaluronic acid, vide Example3.

The saccharide is preferably a polysulphated or persulphated saccharide,which means that two or more sulphur-containing moieties may be presentas substituents on the carbohydrate moiety.

In some cases, the sulphated saccharide may be complexed with or form asalt with a metal, e.g. an alkali or alkaline earth metal such as Na, K,Ca, Sr, Mg or Ba, or Al, Zn, Cu, Ga, Bi and Mn, or with an organic base.The salts are preferably selected from those which are sparingly solublein water, in order to obtain a slow release effect when they are usedtopically in the oral cavity. The currently preferred metal isaluminium, optionally in the form of aluminium hydroxide. In thesulphated saccharide, aluminium complexes with the sulphate moiety.Thus, a preferred class of sulphated saccharides is aluminiumdisaccharide polysulphates of which the currently most preferredsubstance is sucralfate.

Sucralfate may be represented by the following formula: ##STR1##

The substance may, for instance, be prepared as disclosed in U.S. Pat.No. 3,432,489 by reacting a 1-10% aqueous solution of a disaccharidepolysulphate or an alkali metal or alkaline earth metal salt thereofwith a 1-10% aqueous solution containing aluminium ions, preferablyAlCl(OH)₂ at room temperature and a pH of 4-4.5. The disaccharidepolysulphate is prepared by reacting a disaccharide with ClSO₃ H, H₂ SO₄or H₂ SO₄ -C₅ H₅ N.

Sucralfate may also be termed sucrose octakis(hydrogen sulphate)aluminium complex. Its CAS number is 54182-58-0. The commercial productis a white powder which is practically insoluble in water and mostorganic solvents; it is soluble in acids and alkalis. In practice, theremay be slight variations in the chemical composition, for example due tothe fact that the sulphation may be slightly incomplete, giving aproduct that may e.g. contain a certain proportion of molecules whichare not octasulphated (persulphated), but which instead are sulphated toa lesser degree, for example heptasulphated. Such minor variations inthe commercial product are well known and are reflected in the fact thatthe aluminium content in commercial products may range from 17 to 21%and the sulphur content from 9.5 to 12.5%. In the present context, theterm "sucralfate" also comprises such generally accepted minorvariations.

Apart from sulphated saccharides, it is contemplated that othersubstances may show a similar therepeutic or prophylactic activity inconnection with dental diseases and conditions as defined above.Examples of such substances are ketotifen and chromoglycate and otherantiallergic agents known to act on and stabilize cell surfaces, suchagents also being suspected of inhibiting the activity of hyaluronidase.

Although there may be cases where the sulphated saccharide may beadministered as such, it will typically be compounded with one or morepharmaceutically acceptable carriers or excipients to be presented in aform which is suitable for topical application to teeth ortooth-supporting tissue. It will usually be in the form of a fluid,semi-fluid, semi-solid or solid preparation such as a solution,suspension, powder, paste, gel, cream, salve, dental fixative,periodontal implant, chewing gum, chewable tablet, effervescent tabletor lozenge.

The topical preparation may be formulated in accordance withconventional pharmaceutical practice ;with pharmaceutical excipientsconventionally used for topical applications such as alginate, pectin,gelatin and derivatives thereof, cellulose derivatives such as methylcellulose, carboxymethyl cellulose or oxidised cellulose, guar gum,acacia gum, karaya gum, tragacanth gum, locust bean gum, bentonite,agar, carbomer, bladderwrack, ceratonia, dextran and derivativesthereof, ghatti gum, hectorite, isphaghula husk, polyvinylpyrrolidone,silica and derivatives thereof, such as silicates, xanthan gum, kaolin,chalk, dicalcium phosphate, alumina, pyrophosphate, talc, starch andderivatives thereof, paraffin, water, vegetable and animal oils,isopropyl myristate, polyethylene, polyethylene oxide, polyethyleneglycol and polyethylene glycol esters, polypropylene glycol, glycerol,ethanol, propanol, propylene glycol, glycols, alcohols, fatty alcohols,fixed oils, sodium, potassium, aluminium, magnesium or calcium salts(such as the chloride, carbonate, bicarbonate, citrate, gluconate,lactate, acetate, gluceptate or tartrate), rubbers (artificial ornatural) such as chicle, polyisobutylene, etc., sorbitane esters,quaternary ammonium salts, salts of fatty acids and polysorbates.

The preparation of the invention may also contain conventional additivessuch as thickeners, emulsifiers, anionic, cationic and non-ionicsurfactants, stabilizing agents, preservatives, abrasives, flavouringagents, etc.

It has surprisingly been found that a preparation which is particularlyeffective for prophylactic purposes may be prepared by mixing thesulphated saccharide with a toothpaste preparation. The sulphatedsaccharide has been found to be compatible with toothpaste preparationsof the type commonly available as commercial toothpastes, and can thusbe used on a regular basis for the prevention of e.g inflammatory andplaque-related conditions.

A toothpaste will usually contain polishing agents, surfactants, gellingagents and other excipients such as flavouring and colouring agents. Thepolishing agent may be selected from those which are currently employedfor this purpose in dental preparations. Suitable examples arewater-insoluble sodium or potassium metaphosphate, hydrated or anhydrousdicalcium phosphate, calcium pyrophosphate, zirconium silicate ormixtures thereof. Particularly useful polishing agents are various formsof silica, especially silica xerogels such as are described in U.S. Pat.No. 3,538,230. The polishing agent is generally finely divided, with aparticle size smaller than 10 μm, for example 2-6 μm. The polishingagent may be employed in an amount of 10-99% by weight of thetoothpaste. Typically the toothpaste preparations will contain 20-75% ofthe polishing agent.

A suitable surfactant is normally included in the toothpastepreparations. The surfactant is typically a water-soluble non-soapsynthetic organic detergent. Suitable detergents are the water-solublesalts of: higher fatty acid monoglyceride monosulphates (for examplesodium hydrogenated coconut fatty acid monoglyceride monosulphate);higher alkyl sulphates (for example sodium lauryl sulphate);alkylarylsulphonates (for example sodium dodecylbenzene-sulphonates);and higher alkyl sulphoacetates (for example sodium laurylsulphoacetate). In addition, there may be employed saturated higheraliphatic acyl amides of lower aliphatic amino carboxylic acids having12-16 carbon atoms in the acyl radical and in which the amino acidportion is derived from the lower aliphatic saturatedmonoaminocarboxylic acids having 2-6 carbon atoms, such as fatty acidamides of glycine, sarcosine alanine 3-aminopropanoic acid and valine,in particular the N-lauryl, myristoyl and palmitoyl sarcosinatecompounds. Conventional non-ionic surfactants may also be included ifdesired.

The surface active materials are generally present in an amount of about0.05-10l%, typically about 0.5-5%, by weight of the toothpastepreparation.

Typically the liquids of the toothpaste will comprise mainly water,glycerol, sorbitol, propylene glycol or mixtures thereof. Anadvantageous mixture is water and glycerol, preferably with sorbitol. Agelling agent such as natural or synthetic gums and gum-like materials,e.g. Irish Moss or sodium carboxymethylcellulose, may be used. Othergums which may be used are gum tragacanth, polyvinyl-pyrrolidone andstarch. They are usually used in an amount up to about 10%, typicallyabout 0.5-5%, by weight of the toothpaste.

The pH of a toothpaste is substantially neutral, such as a pH of about6-8. If desired, a small amount of a pH-regulating agent, e.g. a smallamount of an acid such as citric acid or an alkaline material may beadded.

The toothpaste may also contain other materials such as solublesaccharin, flavouring oils (e.g. oils of spearmint, peppermint,wintergreen), colouring or whitening agents (e.g. titanium dioxide),preservatives (e.g. sodium benzoate), emulsifying agents, silicones,alcohol, menthol and chlorophyll compounds (e.g. sodium copperchlorophyllin).

The content of sucralfate or other sulphated saccharide in thetoothpaste of the above type or types discussed below will normally bein the range of 1-20% by weight, calculated on the weight of the totaltoothpaste composition, such as in the range of 5-20% by weight, inparticular about 10-20% by weight such as 12-18% by wight. The latterranges are especially indicated for toothpastes which are used fortreatment of gingivitis and periodontosis. It is, however, alsointeresting to provide toothpastes having a lower content of sucralfatewhich will often predominantly be adapted for preventive or prophylacticpurposes. For such purposes, sucralfate content ranges from about 0.1 toabout 5% by weight may be interesting.

A special type of toothpaste are toothpastes which are substantiallyclear gels. Such toothpastes may either contain no polishing agents atall or may contain the polishing agent in such finely divided form thatthe gels will still appear substantially clear. Such gel toothpastetypes may either be used per se or may be combined with toothpastescontaining polishing agents as discussed above.

There are, of course, numerous examples of special toothpastes ordentifrices adapted for special purposes or with special advantages.Thus, e.g., EP 280077 describes a toothpaste which contains stabilizeddicalcium phosphate dihydrate, resulting in a high water absorptioncapacity and an adequate viscosity at low abrasive content; U.S. Pat.No. 4,618,488 discloses stable toothpastes, in particular transparenttoothpastes, which contain amourphous silica and/or silicate abrasivewith specific surface areas, resulting in long term stability of thetransparency of the toothpaste; U.S. Pat. No. 4,632,826 discloses atoothpaste, the polishing agent of which is constituted by a combinationof silicagel and/or precipitated silica and weakly calcined aluminamixture, resulting in a toothpaste with low scratching and abrasioneffect and with high storage stability; U.S. Pat. No. 4,721,614discloses a toothpaste which contains sodium bicarbonate as soleabrasive, thus avoiding excessive abrasive properties and retaining agood storage stability; U.S. Pat. No. 4,702,905 and U.S. Pat. No. 4,716,034 disclose toothpastes which are resistent to syneresis in contactwith polyolefin packaging, which toothpastes are thus suitable forpackaging in e.g. laminate tubes, mechanical dispensers and flexiblesachets; U.S. Pat. No. 4,599,363 discloses a method for wetting anddispersing powders for toothpaste preparations in turbulent liquidmedium, the method preventing formation of lumps and loss of powderedsolids and resulting in high quality toothpaste compositions; U.S. Pat.No. 4,701,319 discloses a toothpaste which has good stability, viscosityand processing properties, the toothpaste containing abrasivecarboxyvinyl polymer, and a carrageenan humectant.

It will be understood that these are only a few examples of toothpasteor dentifrice compositions into which a sulphated saccharide, inparticular sucralfate, may be incorporated in the manner described aboveto obtain the surprising advantages characteristic to the presentinvention, and that the person skilled in the art would be able tocompose any kind of suitable toothpaste or dentifrice composition basedon literature references such as the ones given above and the specificinformation contained herein about suitable manners for incorporatingsulphated saccharides in particular sucralfate into such compositions.

The incorporation of sucralfate or other sulphated saccharide in atoothpaste preparation and other dental or oral preparations may beperformed in many different ways. Often, it will be preferred to form asuspension of sucralfate and combine the sucralfate suspension with theother preparation ingredients in paste form. Alternatively, drysucralfate powder may be mixed with the other preparation components,either first with the dry preparation constituents and subsequently withliquid or semi-liquid preparation constituents, or sucralfate powder perse can be incorporated in an otherwise finished preparation.

In this connection it should be mentioned that while the incorporationof sucralfate or other water-insoluble or sparingly water-solublesulphated saccharides is best performed as described herein taking intoconsideration the physical and chemical properties of the sulphatedsaccharide in particular the particle size considerations mentionedbelow, the incorporation of water-soluble sulphated saccharides, such assodium and potassium salts of sucrose oktakis (hydrogen sulphate) intoothpastes or dentifrices or other preparations discussed herein willnormally be extremely simple and will ordinarily consist in the additionof the sulphated saccharide to the preparation or to constituentsthereof in either dry or dissolved form.

For certain purposes, such as "pocket filling materials", denturefixatives and other preparations which are to stay for prolonged periodsin contact with wounded or infected areas, the preparation isadvantageously one which is capable of adhering to the gingiva,periodontal sulcus/pocket, tooth enamel, dentine, root cement ortooth-supporting tissue on which it is applied, in order to ensure asufficiently intimate contact between the active substance and thesurface in question for a sufficient period of time to obtain anefficient localized action of the sulphated saccharide. Such adhesiveproperties may be obtained by for example incorporating suitable highmolecular weight materials such as pectin, gelatine and methylcelluloseinto the preparation, preferably together with a non-aqueous liquidvehicle such as a medium chain triglyceride, e.g. a triglyceridecomprising acid moieties of a length of about 12-18 carbon atoms.

The preparation may further be one which is biodegradable, meaning thatit is capable of being degraded in the body outside the digestive tract.The biodegradable material present in the preparation is one which givesrise to degradation products which are readily eliminated from the bodyby being metabolized at the cellular level or by disintegrating intosmaller components which are eliminated via the kidneys or metabolizedin the liver etc. Examples of useful biodegradable materials aresynthetic polymers such as polyglycolic acid, polyacetic acid,polylactic acid or copolymers thereof, polycarbonates, polyacetals,polyketals, polyorthoesters, etc., as well as natural polymers such asproteins, e.g. gelatin and collagen, or polysaccharides, e.g. dextran,agarose, pectin, starch, alginates, hyaluronic acid, etc. Thebiodegradability of the preparation is considered to be particularlyadvantageous when the preparation is in the form of a periodontalimplant, as this would obviate the necessity of surgically removing theimplant after the treatment is completed.

Periodontal implants may be prepared by moulding, pressing, extruding,etc. in a manner known per se and subsequently formed into any desiredshape such as a film, thread, strip, wedge or sponge. Preparations forinsertion into periodontal pockets are, however, preferably in the formof a paste or gel, a suitable quantity of which is introduced into thepocket by means of a suitable instrument such as a syringe.

A chewing gum may be prepared by incorporating the sulphated saccharideinto a conventional chewing gum base containing chicle or a syntheticrubber. Similarly, chewable tablets may be prepared by compounding thesulphated saccharide with one or more conventional excipients such assorbitol, xanthan gum, etc.

The pharmacologically active element in sucralfate is probably thenon-aluminium complexed sodium and/or potassium salt of sucroseoctakis(hydrogen sulphate). Since such a salt is soluble in water, itwould seem that a small particle size would be an important factor whenpreparing formulations of the sparingly soluble sucralfate. One way ofachieving a small sucralfate particle size is by means of milling,grinding or disintegrating apparatus, e.g. a three roll mill, where thesucralfate powder is ground, preferably together with a suitable liquidvehicle having a viscosity adapted to effectively suspend the resultingfine particles, and preferably a relatively low vapour pressure so thatno excessive evaporation with resulting agglomeration of the fineparticles will occur, such as a polyalcohol, for example glycerin orpolyethylene glycol. The resulting preparation will normally contain upto 60-70% by weight of sucralfate particles with a fairly uniformparticle size of about 5-10 μm or less (for 95% by weight of thesucralfate), the particles being substantially evenly suspended in thevehicle. Such a paste can then be further suspended in any suitablepharmaceutical preparation using well known pharmaceutical methods.Another starting point for a small particle size sucralfate formulationis sucralfate "filter cake", which is sucralfate containing about 50% byweight of water, and with a particle size of about 5-10 μm or less. Thismaterial can be mixed with, for instance, a water-miscible liquid whichhas a relatively low vapour pressure, such as glycerin, in order toprevent the water from evaporating, and the sucralfate particles willretain their small size. Another important factor to take intoconsideration when preparing formulations of sucralfate and othersulphated saccharides is the strong negative charge of salts of sucroseoctakis(hydrogen sulphate), and probably of most sulphated saccharides.The pharmacological effect of sucralfate, salts of sucroseoctakis(hydrogen sulphate) and other sulphated saccharides probablydepends on this negatively charged entity, and the pharmacologicaleffect of the drug may be reduced by the presence of positively chargedmono- and divalent ions in the vehicle.

The topical preparation to be used for the present purpose generallycomprises the sulphated saccharide in an amount of 0.001-99%, typically0.01-75%, more typically 0.1-20%, especially 1-10% by weight of thetotal preparation. In particular, when the sulphated saccharide issucralfate, a preferred concentration thereof in the preparation isoften from 0.5-50%, especially 0.5-25%, especially 1-5%, such as 1-10%.It is suitably applied 1-10 times a day, dependent on the type andseverity of the condition to be treated. Preparations for application inperiodontal pockets, however, are preferably applied at regularintervals during the entire treatment period.

The preparation may contain other active agents than the sulphatedsaccharide, such as antibiotics, antibacterial or antimicrobial agents,antiviral agents, antimycotic agents, bacteriostatic agents (e.g.sulphonamides), antiseptic agents, disinfectants, local anesthetics oranalgesics, antiinflammatory agents, antineoplastic agents andanticaries agents (e.g. fluoride).

As mentioned above, the sulphated saccharide is indicated for use inconnection with any dental disease or condition initially involvingbacterial colonization, inflammation and/or infection of the teeth ortooth-supporting tissue. The sulphated saccharide may thus be used fortreating or preventing dental caries, dental plaque or calculus,gingivitis, periodontitis, alveolitis, pulpitis and osteomyelitis. Ithas further been shown that the sulphated saccharide may be useful forpreventing post-extractive, post-surgical or post-traumatic wounds orbone resorption, prosthetic irritation, irritation, inflammation orinfection associated with tooth eruption or extraction, cysts andneoplastic conditions originating in the tooth-supporting tissue, andbacterial, mycotic and viral oral infections, and it has been shown tobe effective in the treatment of oral infections such as candida.

The invention is further illustrated by the following non-limitingexamples.

EXAMPLE 1

A topical paste preparation for insertions into periodontal pockets andas fixative for dentures was prepared from the following ingredients:

    ______________________________________                                        Sucralfate *             30    g                                              Pectin                   10    g                                              Gelatin                  10    g                                              Carboxymethylcellulose   10    g                                              Medium-chain triglycerides                                                                             60    g                                              ______________________________________                                         * Provided by Abic Laboratories, Israel, in finely divided form (particle     size: 95% by weight <250 μm).                                         

The finely divided sucralfate was thoroughly mixed with the otheringredients in finely divided form. The medium-chain triglycerides wereadded to the resulting powder to a suitable paste-like consistency and asubstantially homogeneous dispersion of the particulate components.

EXAMPLE 2

A topical paste preparation for insertion into periodontal pockets andas fixative for dentures was prepared from the following ingredients:

    ______________________________________                                        Sucralfate *             10    g                                              Gelatin                  10    g                                              Pectin                   10    g                                              Medium-chain triglycerides                                                                             15    g                                              Hydrogenated coconut oil 15    g                                              ______________________________________                                         * Provided by Farmos Pharmaceutical, Finland, 95% by weight <250 μm.  

The finely-divided sucralfate was thoroughly mixed with the pectin andgelatine in finely divided form. The medium-chain triglycerides andhydrogenated coconut oil were added to the resulting powder to asuitable paste-like consistency and a substantially homogeneousdispersion of the particulate components.

EXAMPLE 3

A topical paste preparation for insertion into infected periodontalpockets was prepared from the following ingredients:

    ______________________________________                                        Sucralfate *             30    g                                              Tetracycline             3     g                                              Hyaluronic acid **       0.3   g                                              Pectin                   10    g                                              Gelatin                  10    g                                              CMC                      10    g                                              Medium-chain triglycerides                                                                             60    g                                              ______________________________________                                         * Provided by Farmos Pharmaceutical, Finland, 95% by weight <250 μm.       ** Obtained from human umbilical cord (Sigma)                            

The finely divided sucralfate was thoroughly mixed with otheringredients in finely divided form. The medium-chain triglycerides wereadded to the resulting powder to a suitable consistency and asubstantially homogeneous dispersion of the particulate components.

EXAMPLE 4

A topical gel preparation was prepared by mixing 15 g of sucralfatepowder supplemented by Guilini Chemie, West Germany, 95% by weight <250μm) with 15 ml of 3% HCl. The mixture formed a translucent adhesive gel.

EXAMPLE 5

A topical gel preparation was made by melting 50 g of gelatine andmixing into it 20 g of the same sucralfate powder as in Example 4.

EXAMPLE 6

A toothpaste preparation was prepared by mixing 15 g of the samesucralfate powder as used in Example 4 with 15 ml of glycerol andadjusting the paste to the desired consistency by adding glycerol after2 days.

EXAMPLE 7

A toothpaste preparation was prepared by mixing 10 g of sucralfate(provided by Guilini Chemie, W. Germany, 95% by weight <250 μm) powderwith 12 ml of water. This mixture was subsequently mixed with 12 g of atoothpaste containing polishing agent (Colgate "Blue Mint").

EXAMPLE 8

A toothpaste preparation was made by mixing 10 g of sucralfate powderwith 70 g of a base prepared in advance and comprising:

    ______________________________________                                        Sodium monofluorphosphate                                                                             .38    %                                              Sodium fluoride         0.11   %                                              Sorbitol (70% sol)      58     %                                              Silicon dioxide         18     %                                              Glycerine (98%)         10.1   %                                              Polyethylene glycol (PEG 600)                                                                         3      %                                              Sodium lauryl phosphat  1.3    %                                              Sodium saccharine       0.3    %                                              Dicalcium phosphat      0.1    %                                              Titanium dioxide        0.01   %                                              Tixocil                 4      %                                              Flavour                 0.7    %                                              ______________________________________                                    

and adjusting the consistency by adding distilled water.

EXAMPLE 9

A toothpaste was prepared by mixing:

    ______________________________________                                        Aluminium abrasive        35     %                                            Sterile water             29.3   %                                            Glycerine                 22     %                                            Sucralfate *              10     %                                            Hydroxyethylcellulose (Natrosol 250 M)                                                                  1.4    %                                            Polyethylene glycol 40 di-isostearat                                                                    1      %                                            Flavour K91-4037          1      %                                            Sodium saccharine         0.4    %                                            ______________________________________                                         * Micronized sucralfate (10 μm) provided by Guilini Chemie, W. Germany

EXAMPLE 10

A chewing gum was prepared by heating a commercial chewing gum to 100°C. and then stirring 10% by weight of sucralfate powder into the meltedgum base. The gum base had the following composition:

    ______________________________________                                        Hydrogen peroxide (solid)                                                                             5      mg                                             Sorbitol                285    mg                                             Mannitol                7      mg                                             Saccharin               0.7    mg                                             ______________________________________                                    

Another sucralfate chewing gum was prepared in the same manner using agum based on chicle, sorbitol, dicalcium phosphate and saccharine.

EXAMPLE 11 Clinical trials

A) A paste according to Example 3 was used for treating 10 cases ofperiodontitis accompanied by 5-10 mm deep, infected (i.e. containingpus) periodontal pockets by introducing the paste into pockets by meansof a spatula, after scaling the calculus from the root surface. Thepaste was left in the pockets for a week, after which the treatment wasrepeated.

On examination 2 days after the initial treatment there was no longerany pus or inflammation of the gingiva and the patients did not complainof any pain or irritation. The depth of the periodontal pockets wasobserved to be reduced. After 2 weeks it was observed that the mobileteeth had become more firmly fixed into the alveole and there were noclinical signs of inflammation.

It was concluded that this paste preparation is suitable for treatingperiodontic disease accompanied by infected periodontal pockets andloosening of the affected teeth. The sticky paste prevents the infectionof the cleaned pocket.

B) A paste according to Example 1 was used substantially as describedunder A) with the exception that the treated periodontal pockets werenot infected, as determined by the absence of pus. As in A), the numberof treated patients was 10.

After a few days the clinical signs of inflammation, bleeding and oedemahad disappeared, the depth of periodontal pockets had been reduced, thetreated teeth had become immobile, and none of the patients hadexperienced clinical side effects of the treatment. 2 weeks later, thedepths of the periodontal pockets had been further reduced.

It is therefore concluded that the paste according to Example 1 iswell-suited for treating periodontal pockets, the more so as thepatient' gingiva were no longer painful, so that they could resumebrushing their teeth and otherwise maintaining a normal oral hygienicstandard.

C) The preparation of Example 2 was used for treating 24 cases ofperiodontitis in which the patients had periodontal pockets of a depthof up to 5-6 mm. After depuration and cleaning the teeth, the gel wasinjected into the periodontal pockets by means of a syringe providedwith a blunt needle.

When examined 2 days later, the patients had not experienced any painafter the treatment, and the inflammation of the gingiva was reduced toan extent normally observed only after a weeks treatment.

D) A toothpaste as described in Example 6 was used in the treatment of100 cases of gingivitis by carefully applying, both with and withoutinitial prophylactic polishing and scaling, the paste on the gingivalmargin for about 2 minutes using a soft bristled toothbrush. Thistreatment was repeated two or more times daily for several weeks(maximum treatment period 6 months).

On examination after a few days an almost healthy gingival mucosa wasobserved, and 50 of the patients who used the toothpaste for longerperiods up to six months showed none of the discolorations of the teethand of the tongue associated with the use of chlorohexidine andantibiotics.

E) A toothpaste according to Example 7 and Example 9 were used by 150patients (75 patients for each toothpaste) constantly or intermittentlyfor periods of from 3 to 12 months (median 6 months), as a soletreatment for gingivitis. The toothpastes were used morning and evening,the gingival margin being brushed horizontally with a soft bristledtoothbrush. The patients were instructed to not rinse their mouth untilone minute after brushing. As a sole treatment, this resulted in healthygingiva with no bleeding and swelling, and a remarkable reduction insubgigival deposits of plaque and calculus has been shown, resulting ina firm binding of the gingiva margin, and thereby effectively preventingfurther progression of periodontic disease.

F) Another 50 patients used the toothpaste of Example 9, but containingonly 2% sucralfate instead of 12% sucralfate. The patient category andthe use of the toothpaste were identical with the above-mentionedExample 11 E), and the anti-gingivitis effect was the same, indicatingthat even a low concentration of 2% sucralfate in a dentifrice wouldseem to be sufficient as a gingivitis-preventing treatment.

G) Pastes according to Example 1 and Example 2 were used as a denturefixative. Twenty patients with difficult upper dentures used the pastesfor periods of up to one year. The pastes have resulted in a goodfixation of the dentures and have had the additional advantages of beingtasteless, providing a long-lasting (up to 12 hours) gluing effect andfunctioning as a kind of shock absorbing paste, with very littleirritation of the gums and mucosa. The pastes have also been used asglue in immediate dentures (immediately after extraction of teeth), andhave given rise to a very quick healing of the gums.

H) The paste of Example 2 and the gel of Example 4 have been used inabout 20 cases of third lower molar eruptions, applying them under themucosal flap. They have resulted in a good anti-inflammatory effectequivalent to the effect seen following the use of chlorohexidine andantibiotics such as Nebaticine.

I) The paste of Example 2 has been used in 25 cases of third lower molarextractions, placed on a gauze mesh, and there has been no incidence ofdry sockets alveolitis.

J) The gel of Example 5 was filled into impression-type syringes. Beforeuse, the syringes were heated to 70° C. in a water-bath, the gel beingused to fill out periodontal pockets. About 10 patients have beentreated, and the effect has been good, with a marked anti-inflammatoryeffect and the pocket being well protected from contamination.

K) The gel preparation of example 4 was used in the gingival margin andleft for 1-2 days, in 50 patients with severe gingivitis with swellingand bleeding, the patients thus being unable to maintain proper oralhygiene. They were instructed not to brush their teeth. Inspection afterone day showed a remarkable healing of the gingivitis, making itpossible to institute the relevant dental treatment without discomfort.The gel acquires a rubber-like consistency and can thus easily beremoved when necessary.

L) The gel of Example 4 has also been used on dentures as a fixative,and it has in a few cases been applied topically on the infected area inthe treatment of oral candida infections. It has also been usedfollowing minor surgery in the oral cavity in about 20 cases, beingapplied on the wound area and providing pain relief and ananti-inflammatory and wound healing effect.

EXAMPLE 12

For the curative management of patients with deep periodontal pockets(more than about 5 mm), which constitute about 20% of all periodontosiscases, it is probably necessary to have a method of treatment which canremove the subgingival bacterial plaque formation and keep the dentalsurface free of new plaque formation for a period of time which issufficiently long to allow the gingival tissue to normalize and thecontact epithelium to be re-created and attach to the tooth. For thatpurpose, a special cleaning system, based on a modified ultra-sonicOdontoson (3 N Special, Lennart Goof A/S, Usserod Molle, 2900 Horsholm,Denmark), has been developed. The apparatus is modified by placing awater jet-pipe nearly parallel with the ultrasonic needle, in such a waythat the water jet stream is directed alongside the ultrasonic needle,hitting the point of the needle. With this construction, it is possibleto direct both the ultrasonic needle and the water jet stream into theperiodontal pocket simultaneously. The combined effect of the ultrasonicneedle being carefully moved over the surface of the pocket and thetooth surface while the water vigorously hits the tip of the needle hasshown to be very effective in removing bacterial plaque from the surfaceof the teeth. The amount of water needed is approximately 30-50 ml perminute. The cleaning effect is significantly improved by addingsucralfate in a concentration of approximately 0.1-1% by weight to theflushing water. The addition of sucralfate also significantly delays theformation of new bacterial plaque, and it is helpful in guiding thedentist when removing the subgingival plaque, in that the water stopsfoaming when the plaque is completely removed.

Six patients with advanced periodontitis and periondontal pockets of adepth of 8-12 mm were treated with the above mentioned cleaning system.Sucralfate 0.1% by weight, in the form of Antepsin Granulate, Farmos,was added to the flushing water. This treatment was repeated atappropriate intervals for up to 4 weeks. In all six cases there was anearly complete healing of the periodontotic conditions. Another sixpatients with the same grade of parodontitis underwent the same cleaningof the periodontal pockets followed by injection of a sucralfate paste(Example 2) using a syringe with a blunt needle. After 7 to 14 days, thedeep periodontal pockets had nearly disappeared and the patients wereclassified as being greatly improved with respect to periodontitis.Inflammatory signs and symptoms had completely disappeared and at afollow up after 4 months, there were no signs of reappearance ofperiodontitis.

EXAMPLE 13

Sucralfate has been shown to be highly effective as an anti-inflammatoryagent and moderately effective as a plaque reducing agent when used as amouthwash.

In a study comprising 13 adults (aged 19-46 years) a 2% by weightaqueous suspension of sucralfate was used 2-3 times daily as a mouthwashfor a period of 12 days. No other oral hygiene was allowed during thistest period of 12 days. No other oral hygiene was allowed during thistest period. Before the start of the study, the participants' teeth werepolished and it was controlled that none of the participants had severegingivitis or calculus. The test persons received 200 ml of mouthwashflavored with peppermint, and were instructed to rinse the mouth with 10ml 2-3 times a day. At the start of the study and after 8 and 12 days,plaque control was made with Diaplak, and gingival bleeding wascontrolled using a periodontal probe to investigate the orifice of thegingival crevice. None of the test persons felt any discomfort duringthe test period, and none experienced foetor ex ore. The results belowsummarize measurements of the gingival index (Lee, 1967, J. Periodont.38: 38-44), and plaque index assessed according to the method of Bay &Ainemo.

The mean plaque index before start and before polishing was 0.69, and1.17, respectively, indicating a very minor increase in dental plaquescore during the test period. The condition of the gingivae after 12days of sucralfate mouthwash as the only means of oral hygiene wasperfect, with no signs of beginning inflammatory changes, and thegingival score was 0 for all 13 test persons. Those persons who smokeddeveloped discoloration of the teeth, but apart form this discolorationthere were no side effects.

From previous experience it is known that withdrawal of all mechanicaloral hygiene procedures in individuals with healthy gingivae for aperiod of 2-4 weeks will result in clinically detectable gingivitis. Onthis basis, it can be concluded that topical administration ofsucralfate in the mouth exerts a beneficial effect, in that sucralfateis capable of effectively preventing the development of gingivitis.

EXAMPLE 14

Double-blind randomized comparison of a sucralfate dentifrice against achlorhexidine dentifrice (active control), and a blue minty geldentifrice (passive control), in adults with mild gingivitis.

The objective of this study was to compare the effect of a 10%sucralfate dentifrice (Example 9) on established gingivitis and plaquewith a blue minty gel (negative control), and Corsodoyl® Gel dentifrice(positive control, 10% chlorhexidine). The subjects were selected frompatients attending a general dental practice. Forty-eight (48) subjectsmeeting the inclusion criteria were randomly allocated to one of thethree groups. The subjects were instructed to use only the allocateddentifrice and toothbrush (Oral B® 35), using enough toothpaste to coverthe head of the brush and to brush for one minute morning and night, andto use no other oral hygienic procedures. The subjects received noprophylaxis before the start of the trial.

Scoring system

The following 6 teeth were scored: 6+, 2+, +4, 4-, -2, -6. Swelling wasscored at the gingival papilla meseally to the teeth. The gingival index(GI) was scored from 0-3 using the Quikly-Hein GI index, and the plaqueindex (PI) was scored from 0-5. Pockets were measured by probing. Foreach tooth, probing was carried out using 3 scores buccaly (distally,midale and meseally) and one score orally (midale). Plaque was scoredusing the Lambster modification of the Quigley-Hein plaque index afterdisclosing the teeth with Diaplak (erythrosine). The figures shown beloware the sum of all 24 measurements for each index.

The above-described procedure was used at week three (3) and at week six(6) examinations.

Results

Baseline scores obtained at the first visit for swelling, gingivitis,plaque and pocket depths showed that all 48 patients had slightinflammatory changes and mild gingivitis.

At each of the three week and at the six week examinations, the effectof the test dentifrices was evaluated on 37 patients. The effect ongingivitis and plaque formation, respectively, is expressed as thechange in the gingival index (GI) and the plaque index (PI) (calculatedas post/pre ×100) during the test period. The effect obtained over thefirst three week period is calculated for patients attending the threeweek visit, and correspondingly, the effect for the six week period iscalculated for patients attending the six week visit. Tables 1 and 2give the mean values for the three groups.

                  TABLE 1                                                         ______________________________________                                        Mean gingival index (GI)                                                              Placebo  Chlorhexidine                                                                            Sucralfate                                        ______________________________________                                        0-3 weeks:                                                                              109%       101%       88%                                           0-6 weeks:                                                                              110%       100%       90%                                           ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Mean plaque index (PI)                                                                Placebo  Chlorhexidine                                                                            Sucralfate                                        ______________________________________                                        0-3 weeks:                                                                              91%        71%        83%                                           0-6 weeks:                                                                              94%        84%        92%                                           ______________________________________                                    

The acceptability and effect of the toothpaste was evaluated by askingthe patients at the three week visit about taste, staining of the teethand tendency to gingival bleeding while brushing. The results are shownin Table 3.

                  TABLE 3                                                         ______________________________________                                        Ratings for taste, staining and bleeding                                                 Number of patients                                                            Placebo Chlorhexidine                                                                             sucralfate                                     ______________________________________                                        Taste: Good      9         0         6                                               Average   6         2         4                                               Bad       0         10        0                                        Staining:                                                                            Less      0         1         2                                               No change 13        2         8                                               More      2         9         0                                        Bleeding:                                                                            Less      3         1         4                                               No change 11        11        6                                               More      1         0         0                                        ______________________________________                                    

Conclusion

Chlorhexidine had some effect on plaque formation, and at the three weekvisit the plaque index for chlorhexidine was reduced to 71% of thebaseline findings. Chlorhexidine gave no reduction in the gingivalindex. The sucralfate dentifrice showed a moderate but consistentbeneficial effect on the gingivae. During the first three weeks of thetest period the gingival index with sucralfate was reduced from a meanof 1.23 to a mean of 1.08, indicting that most of the bleeding sites haddisappeared. There was also some effect of sucralfate on plaqueformation.

The sucralfate dentifrice was generally very well accepted. It was ratedas having a good taste and was reported by some of the test persons togive less bleeding. Nearly all of the patients were positive withrespect to continued use of the sucralfate dentifrice. A few patientsreported spontaneously that the sucralfate dentifrice had a beneficialeffect on tobacco strains.

Chlorohexidine was nearly unanimously rated as having a bad taste andgiving rise to discolouring of the teeth, leading to four out of sixteentest persons using chlorhexidine dropping the test. With few exceptions,the subjects using chlorhexidine would not continue using this testdentifrice.

We claim:
 1. A method of preventing, diminishing or treating dentaldisease in a human, which comprises topically administering into theoral cavity a salve, paste, gel or cream preparation comprising aprophylactically or therapeutically effective amount of an aluminum saltor complex of a sulfated saccharide, said preparation being suitable fordental use.
 2. The method of claim 1, wherein the saccharide is anoligosaccharide.
 3. The method of claim 2, wherein the oligosaccharideis selected from the group consisting of sucrose, lactose, maltose, andcellobiose.
 4. The method of claim 1, wherein the saccharide ispolysulphated.
 5. The method of claim 4, wherein the saccharide ispersulfated.
 6. The method of claim 1, wherein the aluminum is in theform of aluminum hydroxide.
 7. A method of claim 1, wherein thesulphated saccharide is an aluminum disaccharide polysulphate.
 8. Themethod of claim 7, wherein the sulphated saccharide is sucralfate. 9.The method of claim 1, wherein the sulphated saccharide is formulated asa topical preparation.
 10. The method of claim 9, wherein the topicalpreparation additionally contains a non-sulphated polysaccharide. 11.The method of claim 9, wherein the preparation comprises an adhesivewhich is capable of adhering to the teeth or tooth-supporting tissue.12. The method of claim 9, wherein the topical preparation isbiodegradable.
 13. The method of claim 1, wherein the disease isselected from the group consisting of dental caries, dental plaque,gingivitis, periodontitis, alveolitis, pulpitis, osteomyelitis,post-extractive or post-surgical wounds, tooth eruption, boneresorption, prosthetic irritation, cysts or neoplasms originating is thetooth-supporting tissue, and bacterial, mycotic, and viral oralinfections.
 14. The method of claim 9, wherein the topical preparationhas a form selected from the group consisting of a salve, a paste, agel, a cream.
 15. The method of claim 9, wherein the topical preparationis administered together with one or more other active agents selectedfrom the group consisting of an antibiotic, and antibacterial orantimicrobial agent, an antiviral agent, an antimycotic agent, abacteriostatic agent, an antiseptic agent, a disinfectant, a localanesthetic or analgesic, an anti-inflammatory agent, an antineoplasticagent, and an anticarious agent.
 16. The method of claim 10 wherein thenon-sulfated polysaccharide is hyaluronic acid.
 17. The method of claim1 wherein the concentration of sulfated saccharide in the preparation isat least about 1% by weight of the preparation.
 18. The method of claim9 wherein the preparation contains a high molecular weight materialselected from the group consisting of pectin, gelatine andmethylcellulose, and a triglyceride comprising acid moieties of a lengthof 14-18 carbon atoms.
 19. The method of claim 1 in which thepreparation is a dental paste.
 20. A topical salve, paste, gel or creampreparation useful in preventing or treating dental disease in a humanwhich comprises a prophylactically or therapeutically effective amountof an aluminum salt or complex of a sulfated saccharide, saidpreparation being suitable for dental use.
 21. The preparation of claim20, which additionally contains a pharmaceutical excipient.
 22. Thepreparation of claim 20, wherein the saccharide is an oligosaccharide.23. The preparation of claim 20, wherein the oligosaccharide is selectedfrom the group consisting of sucrose, lactose, maltose and cellobiose.24. The preparation of claim 20, wherein the saccharide ispolysulphated.
 25. The preparation of claim 24, wherein the saccharideis persulfated.
 26. The preparation of claim 20, wherein the aluminum isin the form of aluminum hydroxide.
 27. The preparation of claim 20,wherein the sulphated saccharide is an aluminum disaccharidepolysulphate.
 28. The preparation of claim 27, wherein the sulphatedsaccharide is sucralfate.
 29. A preparation of claim 20, wherein thetopical preparation additionally contains a non-sulphatedpolysaccharide.
 30. The preparation of claim 20, wherein the preparationcomprises an adhesive which is capable of adhering to the teeth ortooth-supporting tissue.
 31. The preparation of claim 20, wherein thetopical preparation is biodegradable.
 32. The preparation of claim 20,wherein the disease is selected from the group consisting of dentalcaries, dental plaque, gingivitis, periodontitis, alveolitis, pulpitis,osteomyelitis, post-extractive or post-surgical wounds, tooth eruption,bone resorption, prosthetic irritation, cysts or neoplasms originatingin the tooth-supporting tissue, and bacterial, mycotic, and viral oralinfections.
 33. The preparation of claim 20, wherein the topicalpreparation has a form selected from the group consisting of a salve, apaste, a gel, a cream.
 34. The preparation of claim 20, wherein theconcentration of sulphated saccharide is from about 0.01 to about 75% byweight of the preparation.
 35. The preparation of claim 29 wherein thenon-sulfated polysaccharide is hyaluronic acid.
 36. The preparation ofclaim 20 wherein the concentration of sulfated saccharide in thepreparation is at least about 1% by weight of the preparation.
 37. Thepreparation of claim 20 which contains a high molecular weight materialselected from the group consisting of pectin, gelatine andmethyl-cellulose, and a triglyceride comprising acid moieties of alength of 12-18 carbon atoms.
 38. The preparation of claim 20 which isfurther characterized as a dental paste.
 39. A method of inhibiting theformation of dental plaque which comprises introducing into the oralcavity of a patient a preparation comprising a prophylacticallyeffective amount of a sulfated saccharide, or a salt or complex thereof,said preparation being suitable for dental use.
 40. The method of claim39 wherein the saccharide is an oligosaccharide.
 41. The method of claim39 wherein the preparation comprises a prophylactically effective amountof an aluminum salt or complex of a sulfate saccharide.
 42. The methodof claim 41 wherein the preparation comprises a prophylacticallyeffective amount of sucralfate.
 43. The method of claim 39 wherein thepreparation is a dental salve, paste, gel or cream.
 44. The method ofclaim 39 wherein the concentration of sulfated saccharide in thepreparation comprises at least about 1% by weight of the preparation.45. The method of claim 39 wherein the preparation further comprises anadhesive and is applied to and adheres to the gingiva, periodontalsulcus/pocket, tooth enamel, dentine, root cement or tooth-supportingtissue.
 46. The method of claim 45 wherein the preparation isbiodegradable.
 47. The method of claim 1 wherein the dental disease isgingivitis.
 48. A toothpaste useful in preventing or treating dentaldisease in a human which comprises a therapeutically effective amount ofsucralfate, which is from about 0.1 to about 20% by weight, solubilizedin about 0.05 to about 10% by weight of a water-soluble non-soapsynthetic organic detergent preparation.